CN102432634B - 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex, method for cultivating single crystal of 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex, and application of 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex - Google Patents
2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex, method for cultivating single crystal of 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex, and application of 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex Download PDFInfo
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Abstract
The invention belongs to the technical field of medicinal chemistry, and in particular relates to a 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex, a method for cultivating the single crystal of the 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex, and application of the 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex. A molecular formula of the 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex is C9H18N5O8V, the molecular weight is 375.22, and a structural formula is shown in a formula 1. The 2-amino-4-(2'-pyridine)-pyrimidine-2-peroxo vanadium ammonium salt complex can be applied to anti-diabetic research, has inhibitory action on protein tyrosine phosphatase (PTPase), and has para-insulin activity.
Description
Technical field
The invention belongs to medical chemistry technical field, be specifically related to a kind of 2-amino-4-(2 '-pyridine)-pyrimidine pair and cross vanadyl ammonium salt coordination compound and single crystal cultivation and application.
Background technology
Diabetes are a kind of common endocrinopathys taking metabolism disorders such as sugar, fat and protein as principal character due to defect due to hypoinsulinism in body or effect.The diabetic subject of China has exceeded 4,000 ten thousand in recent years, and diabetes have become and have been only second to cancer and the cardiovascular disorder major disease of serious threat health afterwards in China.Insulin type and some oral adjusting blood sugar medicines are widely used in recent years.
Since last century the eighties, many scholars find that many vanadium metal title complexs have para-insulin activity (C.E.Heyliger, A.G.Tahiliani, J.H.Mcneill, Science, 1985,227 (4693): 1474-477. and S.M.Brichard, F.Assimacopoulos, H.Jeanrenaud, B.Jeanrenaud, Endocrinology, 1992,131 (1): 311-317.).The receptor effect of various countries scholar after to plasma insulin level, insulin receptor function and some insulin actions carries out deep research, abundant experimental results shows after the oral vanadium complex of hyperglycemia animal, blood sugar concentration obviously reduces but plasma insulin level does not become, and this also shows that the effect of lowering blood sugar of vanadium complex is not by stimulating β emiocytosis Regular Insulin to play a role simultaneously.On the other hand, the appearance of organic vanadium title complex has reduced toxicity, has improved effect effect, makes vanadium complex be applied to the clinical possibility that becomes as the novel antidiabetic drug of one.
The people such as Posner report pyridine carboxylic acid diperoxy vanadium potassium and two kinds of compounds of 3-hydroxy-picolinic acid diperoxy vanadium potassium in 1994 can stimulate tumor cell of liver insulin receptor kinase activity (see document: Peroxovanadium compounds:A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics[J] .J.Biol.Chem., 1994, 269 (6): 4596-4604, part-structure is shown in formula 3, comprising part oxa, pic, two peroxide vanadium complexes of bipy and phen are write a Chinese character in simplified form into respectively bpV (oxa), bpV (pic), bpV (bipy) and bpV (phen)), also can suppress the activity of rats'liver endosome Protein-tyrosine-phosphatase (PTPase) simultaneously.The research of Posner shows to have significant arrestin tyrosine phosphatase (PTPase) activity containing the diperoxovandate of bidentate heterocycle.
Formula 3
2000, the result of study that Zhou Xingwang etc. deliver shows that 4 kinds of two peroxide vanadium complex bpV (ox), bpV (bipy), bpV (phen) and pV (pic) rub when grade concentration just to the remarkable (Zhou Xingwang of the activity inhibition of Protein-tyrosine-phosphatase (PTPase) micro-, Chen Zhong, Chen Qingxi, Ye Jianliang, Huang Peiqiang, Wu Qinyi. Acta Biochimica et Biophysica Sinica, 2000,32 (2), 133-138).
Summary of the invention
First object of the present invention is to provide a kind of novel 2-amino-4-(2 '-pyridine)-pyrimidine two vanadyl ammonium salt coordination compounds of crossing, and its molecular formula is C
9h
18n
5o
8v, molecular weight is 375.22, structural formula is as shown in Equation 1.
Formula 1
The unit cell of the above-mentioned two monocrystalline of crossing vanadyl ammonium salt coordination compound of 2-amino-4-(2 '-pyridine)-pyrimidine has the crystalline framework shown in formula 2 and composition.
Formula 2
Second object of the present invention is the cultural method of the two monocrystalline of crossing vanadyl ammonium salt coordination compound of 2-amino-4-(2 '-pyridine)-pyrimidine that provide above-mentioned, this cultural method comprises the step of following order: vanadic salts is reacted with 30% hydrogen peroxide, after disappearing, vanadic salts in solution, adds suitable quantity of water again, add again 2-amino-4-(2 '-pyridine)-pyrimidine, and continue to stir for some time, filter; Filtrate is placed 3～7 days at 0～10 DEG C, obtains the two vanadyl ammonium salt coordination compound crystal of crossing of 2-amino-4-(2 '-pyridine)-pyrimidine; Wherein, the mol ratio of 30% hydrogen peroxide and vanadic salts is 5: 1, and 2-amino-4-(2 '-pyridine)-pyrimidine and vanadic salts are pressed the mixed in molar ratio of 1: 1～1: 1.1, and the concentration of vanadic salts is 0.10～0.40mol/L.
More particularly, described vanadic salts is ammonium vanadate or ammonium meta-vanadate.
The 3rd object of the present invention is the two application of crossing vanadyl ammonium salt coordination compound of 2-amino-4-(2 '-pyridine)-pyrimidine that provides above-mentioned, i.e. its application aspect treatment diabetes.
More particularly, the two vanadyl ammonium salt coordination compounds of crossing of described 2-amino-4-(2 '-pyridine)-pyrimidine in the application aspect treatment diabetes are, are that PTPase is inhibited to Protein-tyrosine-phosphatase, have para-insulin activity.
It is 12 μ mol/L to the 503nhibiting concentration value of PTPase that described 2-amino-4-(2 '-pyridine)-pyrimidine pair is crossed vanadyl ammonium salt coordination compound.
Vanadic salts of the present invention, hydrogen peroxide, part are all commercially available.
Complex monocrystal cultural method of the present invention is simple, material is easy to get, just the activity of Protein-tyrosine-phosphatase (PTPase) is had to remarkable restraining effect micro-rubbing when grade concentration, therefore, title complex of the present invention has para-insulin activity, for the treatment of diabetes provides a kind of new drug development approach.
Embodiment
Below in conjunction with specific experiment example, the present invention is described in further detail.
Embodiment 1: the single crystal cultivation of title complex of the present invention.
In beaker, add 1.2g NH
4vO
3h with 10mL
2o
2(30%), treat NH
4vO
3after disappearance, in solution, add 50mL water again, and under ice-water bath, add 2-amino-4-(2 '-pyridine)-pyrimidine of 1.50 grams, under ice bath, continue to stir 1-2 hour, reaction solution is placed 3～7 days at 0～10 DEG C, separate out orange-yellow crystal, with a small amount of water and washing with alcohol crystallization, obtain fine particulate sterling, obtain two vanadyl ammonium complex monocrystal, productive rate approximately 69% crossed of the present invention.
Embodiment 2: monocrystalline X-ray diffraction test conditions and the result of title complex of the present invention.
The experiment of monocrystalline X-ray diffraction is carried out on Oxford diffractometer, adopt the Cu target of graphite monochromator, temperature is 150K, voltage is within the scope of 40kV, electric current 40mA, to collect independent point diffraction, adopt CryAlisPro Gemini utra System program to carry out the reduction of data of title complex diffracted intensity, carry out absorption correction simultaneously.Application SHELXS-97 and SHELXL-97 routine package carry out structure elucidation, hydrogenation and refine, all non-hydrogen atoms adopt complete matrix method of least squares to carry out structure refinement, all non-hydrogen atoms are all done anisotropy refine, about some other detailed information of crystal is listed in table 1 and table 2.
Table 1 title complex NH
4[OV (O
2)
2(C
9h
8n
4)] 3H
2o structure cell and measuring parameter.
Table 2 title complex NH
4[OV (O
2)
2(C
9h
8n
4)] 3H
2o is strong long
strong angular data [°].
Embodiment 3: the mensuration of title complex 503nhibiting concentration of the present invention.
A. enzyme activity determination.Enzyme activity determination is taking 5mmol/L PNPP (low molecular weight protein) as substrate, damping fluid is 0.1mol/L pH 5.0NaAc-HAc (containing 1mmol/L EDETATE SODIUM salt), after 37 DEG C of reaction 10min, add 0.2mol/L NaOH termination reaction, measure A value with 722 spectrophotometers at 405nm place.Record optical extinction coefficient as 1.73 × 104mol taking pNPP as standard substance
-1.L.cm
-1.Enzyme activity is defined as: the enzyme amount that 37 DEG C time, per minute transforms 1 μ mol/L substrate under said determination condition is a unit of activity.
B. the restraining effect of peroxide vanadium complex to enzyme.In 1mL reaction system, (containing 0.1mol/L, pH 5.0NaAc-HAc damping fluid, 1mmol/L PNPP), adds respectively the freshly prepared title complex of the present invention (bpV (2-NH of different concns
2-pprd)) and bpV (phen) (shown in formula 3) fully mix, in water bath with thermostatic control, be preheated to 37 DEG C, add appropriate Protein-tyrosine-phosphatase (PTPase), at 37 DEG C, react 10min, by 0.2mol/L NaOH termination reaction, measure enzyme activity.Not add two vanadyl excessively, other condition is identical, and the enzyme activity of the control tube of surveying is as 100%; Mensuration adds two enzyme activities of crossing vanadyl pipe.Then try to achieve the 503nhibiting concentration (inhibitor concentration when inhibitory enzyme vigor 50%) of two peroxide vanadium complexes according to inhibition curve.
C. record title complex bpV (2-NH of the present invention according to aforesaid method
2-pprd) 503nhibiting concentration be 12 μ mol/L, and the 503nhibiting concentration value of the known pV (phen) with para-insulin activity is 22 μ mol/L, visible title complex of the present invention can be applicable to anti-diabetic research.
Embodiments of the invention are preferred embodiment of the present invention, the mol ratio that in example, 2-amino-4-(2 '-pyridine)-pyrimidine mixes with vanadic salts can change in 1: 1～1: 1.1 scope, and the concentration of vanadic salts can change within the scope of 0.10～0.40mol/L.Any those skilled in the art are not departing within the scope of technical scheme of the present invention, can utilize the technology contents of above-mentioned announcement to make a little change or be modified to the equivalent embodiment of equivalent variations, in every case be the content that does not depart from technical solution of the present invention, to any simple modification made for any of the above embodiments, still belong to the scope of technical solution of the present invention according to technical spirit of the present invention.
Claims (6)
1. the two vanadyl ammonium salt coordination compounds of crossing of 2-amino-4-(2'-pyridine)-pyrimidine, is characterized in that: its molecular formula is C
9h
18n
5o
8v, molecular weight is 375.22, structural formula as shown in Equation 1:
2. the two vanadyl ammonium salt coordination compounds of crossing of 2-amino-4-according to claim 1 (2'-pyridine)-pyrimidine, it is characterized in that: the two monocrystalline of crossing vanadyl ammonium salt coordination compound of described 2-amino-4-(2'-pyridine)-pyrimidine, the unit cell of described monocrystalline has the crystalline framework shown in formula 2 and composition, its unit cell parameters is as follows: crystallographic system monoclinic, spacer is P21/c
α=γ=90.00 °, β=98.622 (4) °, unit-cell volume is
z=4, R1=0.0916, wR (F2)=0.2173, it is mainly strong long as follows: V (1)-O (1) is good for and is
v (1)-O (5) is good for and is
v (1)-O (4) is good for and is
v (1)-O (2) is good for and is
v (1)-O (3) is good for and is
v (1)-N (1) is good for and is
v (1)-N (2) is good for and is
o (2)-O (4) is good for and is
o (3)-O (5) is good for and is
mainly strong angle is as follows for it: angle O (2)-V (1)-O (3) is 158.81 (17) °, angle O (1)-V (1)-N (1) is 92.84 (17) °, angle O (5)-V (1)-N (1) is 131.92 (18) °, angle O (4)-V (1)-N (1) is 130.90 (16) °, angle O (2)-V (1)-N (1) is 86.30 (15) °, angle O (3)-V (1)-N (1) is 86.85 (17) °, angle O (1)-V (1)-N (2) is 164.44 (16) °, angle O (5)-V (1)-N (2) is 89.57 (16) °, angle O (4)-V (1)-N (2) is 87.36 (15) °, angle O (2)-V (1)-N (2) is 78.94 (14) °, angle O (3)-V (1)-N (2) is 79.87 (15) °, angle O (1)-V (1)-O (5) is 102.03 (18) °, angle O (1)-V (1)-O (4) is 102.78 (18) °, angle O (5)-V (1)-O (4) is 90.12 (18) °, angle O (1)-V (1)-O (2) is 99.62 (18) °, angle O (5)-V (1)-O (2) is 134.12 (18) °, angle O (4)-V (1)-O (2) is 45.56 (15) °, angle O (1)-V (1)-O (3) is 100.73 (19) °, angle O (5)-V (1)-O (3) is 45.71 (19) °, angle O (4)-V (1)-O (3) is 133.48 (18) °, angle N (1)-V (1)-N (2) is 71.63 (14) °, angle O (4)-O (2)-V (1) is 66.56 (19) °, angle O (5)-O (3)-V (1) is 65.9 (2) °, angle O (2)-O (4)-V (1) is 67.88 (19) °, angle C (18)-N (1)-V (1) is 119.6 (3) °, angle C (13)-N (1)-V (1) is 122.0 (3) °, angle O (3)-O (5)-V (1) is 68.4 (2) °, angle C (15)-N (2)-V (1) is 113.7 (3) °, angle C (12)-N (2)-V (1) is 128.7 (3) °,
3. cultivate the method for the two monocrystalline of crossing vanadyl ammonium salt coordination compound of 2-amino-4-as claimed in claim 2 (2'-pyridine)-pyrimidine for one kind, it is characterized in that comprising the step of following order: vanadic salts is reacted with 30% hydrogen peroxide, after disappearing, vanadic salts in solution, adds suitable quantity of water again, add again 2-amino-4-(2'-pyridine)-pyrimidine, and continue to stir for some time, filter; Filtrate is placed 3～7 days at 0～10 DEG C, obtains the two vanadyl ammonium salt coordination compound crystal of crossing of 2-amino-4-(2'-pyridine)-pyrimidine; Wherein, the mol ratio of 30% hydrogen peroxide and vanadic salts is 5:1, the mixed in molar ratio that 2-amino-4-(2'-pyridine)-pyrimidine and vanadic salts are pressed 1:1～1:1.1, and the concentration of vanadic salts is 0.10～0.40mol/L; Described vanadic salts is ammonium vanadate or ammonium meta-vanadate.
4. the two vanadyl ammonium salt coordination compounds of crossing of 2-amino-4-as claimed in claim 1 (2'-pyridine)-pyrimidine, in an application of preparing in medicine, is characterized in that: the two vanadyl ammonium salt coordination compounds of crossing of described 2-amino-4-(2'-pyridine)-pyrimidine are used for the treatment of diabetes.
5. the two vanadyl ammonium salt coordination compounds of crossing of 2-amino-4-according to claim 4 (2'-pyridine)-pyrimidine are in the application of preparing in medicine, it is characterized in that: it is that PTPase is inhibited to Protein-tyrosine-phosphatase that described 2-amino-4-(2'-pyridine)-pyrimidine pair is crossed vanadyl ammonium salt coordination compound, has para-insulin activity.
6. the two vanadyl ammonium salt coordination compounds of crossing of 2-amino-4-according to claim 5 (2'-pyridine)-pyrimidine, in the application of preparing in medicine, is characterized in that: it is 12 μ mol/L to the 503nhibiting concentration value of PTPase that described 2-amino-4-(2'-pyridine)-pyrimidine pair is crossed vanadyl ammonium salt coordination compound.
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| CN106188103B (en) * | 2016-07-14 | 2017-10-13 | 河南中医学院 | A kind of azacyclo- transition metal copper complex containing multiple coordination sites, preparation method and application |
| CN106749393A (en) * | 2017-01-09 | 2017-05-31 | 山西大学 | Picoline hydrazonic acid derivative dioxygen vanadium（V）Complex and preparation method thereof |
| CN108558935B (en) * | 2018-04-08 | 2019-06-14 | 广西师范大学 | Vanadic anhydride crystalline material and its synthetic method based on the modification of tartaric acid chiral derivatives |
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Non-Patent Citations (4)
| Title |
|---|
| DerekA.Beauchampetal..Molecularsquares rectangles and infinite helical chains utilising the simple ‘corner’ligand 4-(2-pyridyl)-pyrimidine.《Chemical Communications》.2002 |
| MasahikoMaekawaetal..Sandwich-shapedsilver(Ⅰ)metallomacrocyclesencapsulatingaXF62-(X=Si Ge and Sn) anion.《Chemical Communications》.2006 |
| Molecular squares, rectangles and infinite helical chains utilising the simple ‘corner’ligand 4-(2-pyridyl)-pyrimidine;Derek A. Beauchamp et al.;《Chemical Communications》;20020926;第2484—2485页 * |
| Sandwich-shaped silver(Ⅰ) metallomacrocycles encapsulating a XF62-(X=Si,Ge and Sn) anion;Masahiko Maekawa et al.;《Chemical Communications》;20060317;第2161—2163页 * |
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